(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have discovered the mechanism
that facilitates how two ion channels collaborate in the control of electrical
signals in the brain. The investigators showed that the channels were
anchored by a third protein at key locations on the nerve cell surface,
allowing them to work together to set the timing and pattern of nerve
impulses. They also found that this channel partnership mechanism is present
in all vertebrates, but is lacking in invertebrates, suggesting that the
coupling of these channels may be essential for the higher abilities of
vertebrate brains. The elucidation of this novel interaction should aid
efforts to develop new treatments for epileptic seizures, pain, and abnormal
muscle movements. They report their findings in the cover article of the
March 8 issue of the Journal of Neuroscience.

Sodium and potassium are salt molecules (or ions) found throughout the
body. Cells pump extra potassium into their interiors, and pump extra
sodium out to the surrounding fluid. Electrical impulses in neurons are
created when these ions are allowed to return to their original locations
by passing rapidly through channels in nerve cells’ outer membranes.
Nerve cells possess wire-like extensions, called axons, which initiate
these impulses and carry them from one cell to the next.

Penn’s Edward Cooper, MD, PhD, Assistant Professor
of Neurology, and colleagues, zeroed in on two key regions of nerve axons
- the initial segment, where each impulse starts, and the nodes of Ranvier,
outlying stations spaced along the axon where the impulse receives an
essential electrical boost - to look for the anchoring. Nerve impulses
begin after exciting inputs are received by the nerve cell - either from
the environment or from other nerve cells in the body. Once adequate input
signals have accrued, the movement of sodium into the cell will start
a nerve impulse at the axon initial segment. In response to this activity,
potassium channels then open, permitting the outward movement of potassium
ions.

“The sodium channel opening at the beginning of a nerve impulse
is like releasing a compressed spring,” Cooper explains. “Without
other influences, there is a tendency to keep reverberating, leading to
additional, unwanted nerve impulses.”

Potassium channels have a calming influence on the nerve. “Potassium
channels work like shock absorbers, holding back sodium channel activity
for a period after each nerve impulse,” Cooper continues. Indeed,
some patients have mutations in potassium channels that decrease this
control, causing excessive nerve firing manifested as epileptic seizures
and uncontrolled muscle movements called myokymia and ataxia.

The efficient and speedy passage of nerve impulses along axons is aided
by the presence of an insulating cover, known as myelin, which maintains
the electrical activity along the entire length of the axon. The nerve
impulse is able to skip across the unmyelinated regions of the axon at
the nodes of Ranvier, with the help of sodium and potassium channels.

“Each nerve impulse receives a huge boost from the influx of additional
sodium ions at these nodes, which allows the signal to be propagated to
the next myelinated region of the axon,” states Cooper.

In a series of chemical tests on the potassium channels located on the
axon initial segment and the nodes of Ranvier, the research team was able
to identify a molecular motif that allows both channel types to link to
a protein called ankyrin-G. Ankyrin-G, in turn, binds tightly to the nerve
cell’s cytoskeleton, ensuring the channels’ stabilization
at the initial segment. The chemical motif identified in the potassium
channels was nearly identical to that previously discovered in sodium
channels, revealing that the potassium and sodium channels link to the
ankyrin-G protein in a similar manner.

“The ankyrin-G-interaction with potassium and sodium channels establishes
a unique domain of the cell for initiating the nerve impulse and for boosting
the impulse across the nodes of Ranvier,” states Cooper.

A comparison of several vertebrate and invertebrate channels led to the
discovery that the ankyrin-G interaction is present only in vertebrate
species. The chemical motif present in vertebrates did not exist in the
potassium channels or sodium channels of invertebrates. This comparison
led Cooper and colleagues to realize that the evolutionary split between
vertebrates and invertebrates, as demonstrated by this difference in the
organization of sodium and potassium channels along neurons, occurred
during a similar period in evolutionary history as the appearance of myelin.

“Myelination and the coupling of axonal sodium and potassium channels
are fundamental improvements in the nervous system, and these changes
are probably necessary for the vertebrate ‘life-style’,”
explains Cooper. “You can only be large and fast-moving if you have
a nerve impulse mechanism that is both rapid and highly reliable.”

By understanding the relationship between potassium and sodium channels,
Cooper and colleagues are working to create new treatments for neurological
diseases based on reestablishing the type of nerve-cell impulse control
seen in unaffected individuals. In fact, a new drug that acts by increasing
the openings of these potassium channels is now undergoing U.S. and international
trials for epilepsy, and such agents are also being developed for other
neurological and psychiatric conditions.

Study co-authors are Zongming Pan, Tingching Kao, Zsolt Horvath, Julia
Lemos, Jai-Yoon Sul, Stephen D. Cranstoun, and Steven S. Scherer, all
from Penn, as well as Vann Bennett from Duke University and the Howard
Hughes Medical Institute. This research was funded in part by the National
Institutes of Health, the Whitaker Foundation, and the University of Pennsylvania
McCabe Foundation.

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